Sleep deprivation induces anxiety-like behaviors through IL-6 driven astrocyte-GABAergic neuron crosstalk in the PAG-ACC circuit

  • J Neuroinflammation. 2026 May 22;23(1):250. doi: 10.1186/s12974-026-03879-z.
Xiao Xu  #  1 ,  Ziang Wu  #  1 ,  Wenxin Hang  1  2 ,  Shaojia Mao  1 ,  Jiahui Sun  1  3 ,  Huanbin Xiong  1 ,  Jinpiao Zhu  4 ,  Daqing Ma  5  6
Affiliations
  • 1. Perioperative and Systems Medicine Laboratory, Department of Rehabilitation, Department of Anesthesiology, Children's Hospital, National Clinical Research Center for Children and Adolescents' Health and Diseases, Zhejiang University School of Medicine, Hangzhou, 310015, China.
  • 2. Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
  • 3. Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China.
  • 4. Perioperative and Systems Medicine Laboratory, Department of Rehabilitation, Department of Anesthesiology, Children's Hospital, National Clinical Research Center for Children and Adolescents' Health and Diseases, Zhejiang University School of Medicine, Hangzhou, 310015, China. [email protected].
  • 5. Perioperative and Systems Medicine Laboratory, Department of Rehabilitation, Department of Anesthesiology, Children's Hospital, National Clinical Research Center for Children and Adolescents' Health and Diseases, Zhejiang University School of Medicine, Hangzhou, 310015, China. [email protected].
  • 6. Division of Anesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK. [email protected].
  • # Contributed equally.
PMID: 42174628 DOI: 10.1186/s12974-026-03879-z
Abstract

Sleep deprivation (SD) is associated with anxiety-like behaviors, yet the underlying molecular and neural circuit mechanisms remain unclear. Using a 24-hour SD paradigm in mice, we found that SD induced anxiety-like behaviors and increased interleukin-6 (IL-6) in blood and the periaqueductal gray (PAG), and PAG-targeted administration of IL-6 receptor antagonist rescued the anxiety-like behaviors. This increased IL-6 activated PAG astrocytes, as evidenced by morphological remodeling, increased calcium activity, and enhanced glutamate release. Astrocytic activation upregulated several genes associated with endoplasmic reticulum (ER) protein synthesis and processing, including neuronal mesencephalic astrocyte-derived neurotrophic factor (Manf). Knockdown of Manf in PAG neurons upregulated the GABAA receptor α1 subunit (Gabra1), reduced the activity of GABAergic neurons projecting to the anterior cingulate cortex (ACC), and rescued anxiety-like behaviors. Chemogenetic inhibition of this PAG-ACC circuit prevented SD-induced anxiety-like behaviors, whereas its activation recapitulated the anxiety-like behaviors. Our study identifies an IL-6-astrocyte-Manf signaling axis in the PAG that drives anxiety-like behaviors via enhanced GABAergic neuronal output to the ACC. This PAG-ACC circuit may serve as a neuroimmune hub for SD-mediated anxiety-like behaviors and represents a potential therapeutic target.

Keywords
Anxiety; IL-6; Mesencephalic astrocyte-derived neurotrophic factor; Periaqueductal gray; Pro-inflammatory cytokine; Sleep deprivation.
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